2-106413119-A-G

Variant names:

• chr2-106413119-A-G
• rs1200568186
• NM_001144013.2:c.5231T>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_001144013.2(RGPD3):​c.5231T>C​(p.Leu1744Pro) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0026 (0 hom., cov: 29)
  • Exomes 𝑓: 0.0025 (164 hom.)
  • Failed GnomAD Quality Control
• Consequence: RGPD3 NM_001144013.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 5.67
• Publications: 0 publications found

Genes affected

RGPD3 (HGNC:32416): (RANBP2 like and GRIP domain containing 3) This gene is located in a cluster of Ran-binding protein related genes on chromosome 2 which arose through duplication in primates. The encoded protein contains an N-terminal TPR (tetratricopeptide repeat) domain, two Ran-binding domains, and a C-terminal GRIP domain (golgin-97, RanBP2alpha, Imh1p and p230/golgin-245) domain. [provided by RefSeq, Sep 2011]

ENSG00000291125 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0046307743).
• BP6: Variant 2-106413119-A-G is Benign according to our data. Variant chr2-106413119-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 2360286.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RGPD3	NM_001144013.2	c.5231T>C	p.Leu1744Pro	missense_variant	Exon 22 of 23	ENST00000409886.4	NP_001137485.1
RGPD3	XM_017004738.2	c.5255T>C	p.Leu1752Pro	missense_variant	Exon 23 of 24		XP_016860227.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RGPD3	ENST00000409886.4	c.5231T>C	p.Leu1744Pro	missense_variant	Exon 22 of 23	1	NM_001144013.2	ENSP00000386588.4

Frequencies

GnomAD3 genomes AF: 0.00266 AC: 398 AN: 149848 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00104

Gnomad AMI AF: 0.00221

Gnomad AMR AF: 0.00193

Gnomad ASJ AF: 0.00888

Gnomad EAS AF: 0.0122

Gnomad SAS AF: 0.0140

Gnomad FIN AF: 0.0000948

Gnomad MID AF: 0.0338

Gnomad NFE AF: 0.00226

Gnomad OTH AF: 0.00442

GnomAD2 exomes AF: 0.00301 AC: 749 AN: 249134 AF XY: 0.00311

Gnomad AFR exome AF: 0.00102

Gnomad AMR exome AF: 0.00241

Gnomad ASJ exome AF: 0.00390

Gnomad EAS exome AF: 0.0106

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00149

Gnomad OTH exome AF: 0.00514

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00248 AC: 3589 AN: 1449766 Hom.: 164 Cov.: 31 AF XY: 0.00300 AC XY: 2161 AN XY: 720504

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000900 AC: 30 AN: 33316

American (AMR) AF: 0.00237 AC: 105 AN: 44390

Ashkenazi Jewish (ASJ) AF: 0.00821 AC: 209 AN: 25454

East Asian (EAS) AF: 0.0134 AC: 502 AN: 37536

South Asian (SAS) AF: 0.0153 AC: 1281 AN: 83758

European-Finnish (FIN) AF: 0.000807 AC: 43 AN: 53286

Middle Eastern (MID) AF: 0.0187 AC: 74 AN: 3954

European-Non Finnish (NFE) AF: 0.00103 AC: 1147 AN: 1108522

Other (OTH) AF: 0.00332 AC: 198 AN: 59550

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00263 AC: 395 AN: 149958 Hom.: 0 Cov.: 29 AF XY: 0.00275 AC XY: 201 AN XY: 73212

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00104 AC: 43 AN: 41270

American (AMR) AF: 0.00193 AC: 29 AN: 15038

Ashkenazi Jewish (ASJ) AF: 0.00888 AC: 29 AN: 3264

East Asian (EAS) AF: 0.0122 AC: 60 AN: 4900

South Asian (SAS) AF: 0.0136 AC: 61 AN: 4494

European-Finnish (FIN) AF: 0.0000948 AC: 1 AN: 10554

Middle Eastern (MID) AF: 0.0326 AC: 9 AN: 276

European-Non Finnish (NFE) AF: 0.00226 AC: 152 AN: 67202

Other (OTH) AF: 0.00438 AC: 9 AN: 2056

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00349 Hom.: 4

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Nov 16, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	20
DANN	Benign	0.059
DEOGEN2	Benign	0.0040	.;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.22	T;T
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.0046	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-2.7	.;N
PhyloP100		5.7
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	1.1	.;N
REVEL	Benign	0.15
Sift	Benign	1.0	.;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	.;B
Vest4		0.33
MutPred		0.44		.;Gain of glycosylation at L1744 (P = 0.0146);
MVP		0.072
ClinPred		0.011	T
GERP RS		1.1
Varity_R		0.090
gMVP		0.15
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1200568186; hg19: chr2-107029575;